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Inflammation

, Volume 42, Issue 6, pp 2105–2118 | Cite as

GSK-3β Inhibitor Induces Expression of the TLR4/MyD88/NF-κB Signaling Pathway to Protect Against Renal Ischemia-Reperfusion Injury During Rat Kidney Transplantation

  • Shuai Su
  • Peng Zhang
  • Qilin Zhang
  • Zhikang YinEmail author
Original Article

Abstract

Ischemia-reperfusion injury (IRI) is an inevitable consequence of kidney transplantation (KT). The aim of our study was to investigate the protective effect of a glycogen synthase kinase 3β (GSK-3β) inhibitor against cold IRI in a rat renal transplantation (RT) model and a rat cold-IRI model through the toll-like receptor 4 (TLR4)/myeloid differentiation factor 88 (MyD88)/nuclear factor κ-light-chain-enhancer of the activated B cell (NF-κB) signaling pathway. We treated Sprague Dawley (SD) rats in the RT and cold-IRI models with 5 mg/kg and 1 mg/kg, respectively, of the GSK-3β inhibitor 4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione (TDZD-8). We then measured inflammatory factors, i.e., tumor necrosis factor alpha (TNF-α) and interleukins-1β and IL-6 (IL-1β, IL-6), as well as oxidative stress markers, i.e., superoxide dismutase (SOD) and malondialdehyde (MDA), in serum and kidneys. Renal function tests and pathological examinations were performed at 0, 1, 2, 3, and 7 days after RT or cold IRI. We measured expression of TLR4, MyD88, inhibitor of NF-κB kinase (IκB), phosphorylated IκB (p-IκB), NF-κB p65, p-p65, GSK-3β, and phosphorylated GSK-3β (p-GSK-3β) by Western blot and immunohistological staining. After intervention with the GSK-3β inhibitor, renal function was improved; oxidative stress injury was reduced; expression of p-GSK-3β was upregulated; expression of p-IκB, TLR4, MyD88, and p-p65 was downregulated; pathological damage was significantly reduced; and expression of TNF-α, IL-1β, and IL-6 messenger ribonucleic acid (mRNA) was downregulated. These results strongly suggested that GSK-3β might be a key target for the treatment of IRI in KT. The GSK-3β inhibitor inhibited phosphorylation of NF-κB p65 and IκB by inhibiting the TLR/MyD88 pathway, reducing oxidative stress injury and the production of downstream inflammatory factors.

KEY WORDS

glycogen synthase kinase 3β TLR4/MyD88/NF-κB pathway renal ischemia-reperfusion injury kidney transplantation 

Notes

Compliance with Ethical Standards

All animal procedures for this study were performed strictly according to the Guide for the Care and Use of Laboratory Animals and were approved by the Animal Care and Use Committee of Chongqing Medical University, Chongqing, China.

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Shuai Su
    • 1
  • Peng Zhang
    • 2
  • Qilin Zhang
    • 1
  • Zhikang Yin
    • 1
    Email author
  1. 1.Department of UrologyThe First Affiliated Hospital of Chongqing Medical UniversityChongqingChina
  2. 2.Department of Forensic MedicineHainan Medical UniversityHaikouChina

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